The Cardiometabolic microRNA Laboratory studies how microRNAs alter the expression of key genes involved in the pathogenesis of atherosclerosis and other chronic inflammatory diseases, such as type II diabetes. The team also studies novel mechanisms of inflammation that promote plaque vulnerability. We employ animal models of human disease, in vitro assays of inflammation, cholesterol homeostasis and cellular activation, and analyze pathways of interest in human plasma and atherosclerotic plaque samples.
The laboratory is funded by the Canadian Institutes of Health Research (CIHR), the Ontario Ministry of Research and Innovation, and the JP Bickell Foundation.
Driven by the interplay between accumulation of excess cholesterol in the arterial wall and the immune system, atherosclerosis is a disease of maladaptive inflammation. The atherosclerotic plaque grows when the rate of macrophage accumulation (via recruitment and proliferation) exceeds that of removal (e.g., via cell death and egress). The removal of excess cholesterol is intricately linked to the inflammatory status of lesions, which in turn underlies the susceptibility to plaque rupture- the ultimate clinical complication of atherosclerosis. Our laboratory recently discovered the role of microRNAs as major regulators of macrophage function in atherosclerosis progression. We have identified the unique coupling of microRNAs to the metabolic and energy control of macrophages and cholesterol removal from lesions, and these discoveries open entirely new avenues to attenuate or reverse the atherosclerotic plaque and its resultant complications. The overall goals of my research program are to discover novel mechanisms that underlie plaque progression and vulnerability, and translate these into tools to ameliorate its clinical impact.
Accordingly, our research program focuses on three integrated research themes: (1) how microRNAs alter macrophage function via extracellular signalling mechanisms; (2) how energy metabolism and metabolic dysregulation within inflammatory cells contributes to atherosclerosis; and (3) how inflammation triggers plaque instability and how this can be used as a diagnostic tool for patients with atherosclerotic disease.
Theme #1: Elucidation and therapeutic targeting of extracellular microRNA mechanisms in macrophages
Research objectives: The power of miRNA-based post-transcriptional regulation is amplified by the fact that miRNAs can be secreted into the extracellular space to serve as second messengers of cellular communication to neighbouring and distant cells3. We find that a number of miRNAs are significantly enriched or down-regulated in foam cell exosomes and are predicted to regulate inflammatory pathways and macrophage polarization (M1/M2). We are testing how miRNA-loaded exosomes alter macrophage function in vitro and the propagation of inflammation in atherosclerosis in vivo. We will aim to develop therapeutic anti-sense miRNA and lipid nanoparticles (LNPs) that mimic exosomes for delivery of miRNAs for therapeutic use which are amenable to in vivo imaging if labelled with PET or SPECT tracers that we are currently developing.
Theme #2: Investigating energy metabolism and metabolic dysregulation in inflammatory cells in atherosclerosis
Research objectives: We are examining the role of energy-regulating miRNAs in macrophage cholesterol efflux, reverse cholesterol transport and macrophage inflammation. The metabolic status of a cell is a strictly regulated process. For macrophages in the atherosclerotic plaque, metabolic stress comes in the form of excess cholesterol accumulation, and boosting efflux pathways is necessary to effectively remove and detoxify cholesterol to ultimately reduce the progression of inflammation and plaque development. We have previously identified miR-33 as a miRNA that regulate HDL-cholesterol homeostasis and atherosclerosis (Figure). Now we have discovered that miR-33 globally regulates cellular energy status by controlling mitochondrial ATP production and oxidative phosphorylation. We are now studying energy-regulating miRNAs for their role in macrophage cholesterol efflux and inflammatory status. Given that the metabolic pathways that drive atherosclerosis are inextricably linked with those that drive type 2 diabetes, we can extend the discoveries from these metabolic-miRNA pathways in macrophages to models of insulin resistance, as we have done previously with miR-33.
- Rayner KJ. miR-155 in the Heart: The Right Time at the Right Place in the Right Cell. Circulation. 2015 Apr 7.
- Karunakaran D, Rayner KJ. MicroRNAs in cardiovascular health: from order to disorder. Endocrinology. 2013 Nov;154(11):4000-9.
- Rafatian N, Karunakaran D, Rayner KJ, Leenen FH, Milne RW, Whitman SC. Cathepsin G deficiency decreases complexity of atherosclerotic lesions in apolipoprotein E-deficient mice. Am J Physiol Heart Circ Physiol. 2013 Oct 15;305(8):H1141-8.
- Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, Moore KJ. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013 Aug;14(8):812-20.
- Rayner KJ, Esau EC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE, Moore KJ. Inhibition of miR-33a and b in non-human primates raises plasma HDL cholesterol and reduces VLDL triglycerides. Nature. 2011; 478(7369):404-7.
- Rayner KJ, Sheedy FJ, Esau EC, Hussain FN, Temel RE, Parathath, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in Mice Promotes Reverse Cholesterol Transport and Regression of Atherosclerosis. Journal of Clinical Investigation. 2011; 21(7):2921-31.
- Rayner KJ*, Suarez Y*, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ# and Fernandez-Hernando C#. miR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science. 2010; 328(5985):1570-3. *,# Equal contribution.
- Duewell P*, Kono H*, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V and Latz E. NLRP3 inflamasomes are required for atherogenesis and activated by cholesterol crystals that form early in disease. Nature. 2010; 464(7293):1357-61. * Equal contribution.
Current Team Members
Anne-Claire Duchez, PhD, Postdoctoral Fellow
Denuja Karunakaran, PhD, Postdoctoral Fellow
Adil Rasheed, PhD, Postdocoral Fellow
My Anh Nguyen, MSc, PhD candidate
Leah Susser, MSc candidate
Michele Geoffrion: Laboratory Manager